Abstract 5614: Advancing treatment for brain tumors and metastases with brain permeable SHP2 inhibitor I-1000233

Background: SHP2, a non-receptor protein tyrosine phosphatase encoded by PTPN11, plays a pivotal role as a downstream effector of receptor tyrosine kinases (RTKs) in the MAPK signaling cascade. We report the discovery of I-1000233, a potent and selective SHP2 allosteric inhibitor that is orally bioavailable and penetrates the blood-brain barrier (BBB). This compound holds great potential for treating primary brain tumors and brain metastases associated with dysregulated RTK/RAS/ERK signaling pathways. Experimental Procedures: Through iterative optimization of the physicochemical and pharmacological properties of a lead compound series, we identified I-1000233 as a SHP2 inhibitor with excellent drug-like characteristics. Preclinical studies included in vitro assays to assess potency, in vivo pharmacokinetics to confirm BBB penetration, and proof-of-concept studies in orthotopic xenograft models of glioblastoma and brain metastases. Combination studies were conducted using other brain-penetrant agents targeting the MAPK pathway. Additionally, patient-derived glioblastoma stem cell (GSC) models were collected to refine a responder identification (ID) strategy for potential application in personalized medicine. Results: I-1000233 demonstrated potent in vitro inhibition of SHP2 activity (IC50 = 2 nM) with prolonged target residence time. In vivo, the compound exhibited strong anti-tumor activity in orthotopic glioblastoma and brain metastasis models, both as a monotherapy and in combination with other brain-permeable inhibitors, underscoring its versatility and potential for combination treatment regimens. Moreover, I-1000233 showed efficacy not only in targeting tumor cells bearing EGFR/RAS/MAPK mutations but also in modulating the tumor microenvironment (TME), enhancing the overall anti-tumor response. Further studies using patient-derived GSC models were conducted to identify biomarkers predictive of response, facilitating the development of precision medicine approaches for SHP2-targeted therapies. Conclusions: I-1000233 is a potent, selective, and orally available SHP2 inhibitor with demonstrated efficacy in preclinical models of primary brain tumors and metastases. Its ability to penetrate the BBB, modulate the tumor microenvironment, and provide combinatory potential with other agents highlights its promise as a therapeutic candidate for treating SHP2-responsive brain cancers. Citation Format: Francesca Puca, Alina Ciammaichella, Danilo Fabbrini, Martina Nibbio, Antonino Cucinotta, Giulio Auciello, Francesco Scalabrì, Christian Montalbetti, Alessia Petrocchi, Alessandro Carugo, Carlo Toniatti. Advancing treatment for brain tumors and metastases with brain permeable SHP2 inhibitor I-1000233 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5614.